The long-term objective of these studies is to elucidate the mechanisms underlying the protective effect of estrogen on the cardiovascular system. The risk of heart disease in women increases significantly after menopause. The administration of estradiol-17beta or Premarin as estrogen replacement to postmenopausal women is in widespread use. Undoubtedly the protective effect of estrogen on the cardiovascular system is complicated and multifactorial. The vascular smooth muscle cell, a major site of regulation, is the focus of this proposal. In a recent study we have shown that estradiol-17beta administration to ovariectomized rats shifts the isomyosin composition in uterine smooth muscle to an isoform associated with an increased shortening velocity. In a preliminary experiment we have observed a similar response of the isomyosin population in rat aorta to estrogen. Our specific objective in this proposed study is to examine the effect of estrogen on the isomyosin composition and functional properties of conducting (aorta) and resistance (mesenteric) arteria. Our experimental model consists of estrogen deprivation by bilateral ovariectomy and replacement by estrogen (estradiol-17beta and Premarin) administration. Our central hypothesis is that estrogen alters the isomyosin population which in turn alters the crossbridge cycle rate and velocity of shortening. Changes in cross- bridge cycle parameters can alter the Ca2+-sensitivity of force development which could have a significant impact on the responsiveness of the vascular system and the development of cardiovascular disease. In the second phase we will examine functional parameters in detail using both intact and permeabilized tissue to localize the site of action of estrogen. Detailed biochemical studies of the relation between ATPase activity and isomyosin composition will be correlated with the functional data. We will also compare the response of coronary arteries to estrogen with that of other vascular systems utilizing tissues from sheep. Finally, with this information we will evaluate the role of estrogen in modifying the response of arterial tissue to hypertensive stress, extending our previous studies with the aldosterone-salt model of hypertension. These proposed experiments will provide us with significant new information on the role of the smooth muscle cell and its myosin heavy chain isoform population in the protective effect of estrogen on the cardiovascular system.